Study protocol for supplementation of single high dose Vitamin D in deficient critically ill children and assessment of their short-term outcome: An open label randomized control trial

Keta Vagha; Sham Lohiya; Jayant Vagha; Sunita Vagha; Amar Taksande; Richa Chaudhary

doi:10.12688/f1000research.138765.1

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Study Protocol

Study protocol for supplementation of single high dose Vitamin D in deficient critically ill children and assessment of their short-term outcome: An open label randomized control trial

[version 1; peer review: 1 approved with reservations, 1 not approved]

Keta Vagha ¹, Sham Lohiya¹, Jayant Vagha¹, Sunita Vagha¹, Amar Taksande¹, Richa Chaudhary¹

Keta Vagha ¹, Sham Lohiya¹, [...] Jayant Vagha¹, Sunita Vagha¹, Amar Taksande¹, Richa Chaudhary¹

PUBLISHED 29 Aug 2023

Author details Author details

¹ Pediatrics, Jawaharlal Nehru Medical College, Wardha, Maharashtra, 442001, India

Keta Vagha
Roles: Data Curation, Methodology, Project Administration, Writing – Original Draft Preparation

Sham Lohiya
Roles: Conceptualization, Writing – Review & Editing

Jayant Vagha
Roles: Writing – Review & Editing

Sunita Vagha
Roles: Supervision, Writing – Review & Editing

Amar Taksande
Roles: Writing – Review & Editing

Richa Chaudhary
Roles: Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

This article is included in the Datta Meghe Institute of Higher Education and Research collection.

Abstract

Vitamin D is a fat-soluble vitamin and is classically considered to play a major role in bone metabolism and maintaining Calcium and phosphorus equilibrium. With progressing research, other roles of Vitamin D are surfacing. The pleotropic functions of Vitamin D regulate cell proliferation, differentiation, apoptosis, and angiogenesis. In critically ill children, Vitamin D deficiency is associated with poor outcomes in the form of increased PICU stay, increased duration of mechanical ventilation, higher rate of Ventilator Associated Pneumonias, increased incidence of sepsis, higher intensive care scores and increased incidence of end organ dysfunction. With this background, we aim to conduct an open label Randomized Control Trial to study the short-term outcome of Vitamin D deficient critically ill children after supplementation of a single high dose oral Vitamin D. This will be an open label randomized control trial conducted at a tertiary care hospital in central India. Children aged 1 month to 18 years, admitted in the pediatric intensive care unit with Serum Vitamin D level less than 20 ng/dL will be the study group. These children will be randomized into two groups as per the computer-generated randomization. Group A will receive standard treatment protocol with 10,000 IU/Kg to 400,000 IU (maximum) Vitamin D via mouth or nasogastric tube, whereas Group B will receive standard treatment protocol. Urinary calcium-creatinine ratio will be done on day 3 in Group A to check for hypervitaminosis D. The outcome of both the groups will be assessed. All the data will be added to a Microsoft Excel sheet. Results and interpretation will be determined on the basis of the obtained observation.
Trial registration: CTRI/2022/10/046556.

Keywords

Vitamin D, Steroid hormone, Critically ill children, study protocol, Intensive care

Corresponding author: Keta Vagha

Competing interests: No competing interests were disclosed.

Grant information: Funding has been received from the Research and Development Department, Datta Meghe Institute of Higher Education and Research (DMIHER(DU) R&D/2022/511).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2023 Vagha K et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Vagha K, Lohiya S, Vagha J et al. Study protocol for supplementation of single high dose Vitamin D in deficient critically ill children and assessment of their short-term outcome: An open label randomized control trial [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2023, 12:1047 (https://doi.org/10.12688/f1000research.138765.1) First published: 29 Aug 2023, 12:1047 (https://doi.org/10.12688/f1000research.138765.1) Latest published: 19 Mar 2024, 12:1047 (https://doi.org/10.12688/f1000research.138765.2)

Introduction

Vitamin D is a fat-soluble vitamin and is classically considered to play a major role in bone metabolism and maintaining calcium and phosphorus equilibrium.¹ With progressing research, other roles of Vitamin D are surfacing. This has been driven by the presence of Vitamin D receptors for cholecalciferol on most body tissues.² The pleotropic functions of Vitamin D include regulation of expression of genes in many organs like immune cells, brain, colon, kidneys etc. which are of importance in critically ill children. These added functions of Vitamin D regulate cell proliferation, differentiation, apoptosis, and angiogenesis.³ These non-skeletal actions of vitamin D are similar to that of steroid hormones therefore Vitamin D is considered equivalent to a steroid hormone than just a vitamin.⁴ The majority of Vitamin D requirement is fulfilled by exposure to sunlight and lesser amount is obtained through diet. Despite sufficient sunlight in India, prevalence of Vitamin D deficiency is accounted to be 50% of critically ill children.⁵ In critically ill children, Vitamin D deficiency is associated with poor outcome in form of increased PICU stay, increased duration of mechanical ventilation, higher rate of Ventilator Associated Pneumonias, increased incidence of sepsis, higher intensive care scores and increased incidence of end organ dysfunction.⁵^–¹⁰

There have been many studies conducted to determine the outcome of critically ill Vitamin D deficient children but there is a sparse data about the outcome of these children after supplementation of Vitamin D therefore we wish to take up this study. There are multiple dosing regimens and routes of administration of Vitamin D. In most of the studies, cholecalciferol was used from 200 to 540,000 IU in oral or intramuscular injection form either in single or multiple doses. The daily supplementation of Vitamin D takes months to replenish the body stores but there is a need of its rapid optimization in critically children if we desire its immunomodulatory function.¹¹ A systematic review and meta-analysis conducted by Mc Nally et al. studied more than one hundred research studies, from which it was inferred that Vitamin D at a dose of 10,000 IU/Kg to maximum up to 400,000 IU is associated with no adverse effects. Therefore in our study we will be using this dosing regimen.¹² With this background, we aim to conduct an open label Randomized Control Trial to study the short-term outcome of Vitamin D deficient critically ill children after supplementation of a single high dose oral Vitamin D.

Objectives

The main objective of this study is to assess the short-term outcome of Vitamin D deficient critically ill children after supplementation of single high dose oral Vitamin D. Secondly, to determine the prevalence of Vitamin D deficiency in critically ill children in our area (Central India) and lastly, to assess the effect of single high dose oral Vitamin D supplementation on the immediate outcome.

Methods

Research questions

1. Can supplementation of single dose Vitamin D orally, improve the short term outcome in critically ill children?
2. What is the prevalence of Vitamin-D deficiency in critically ill children in our area (Central India).
3. What is the effect of single high dose oral Vitamin D supplementation on the immediate outcome?

Study design

This will be an open-label randomized control trial. This study will be conducted at Acharya Vinoba Bhave Rural Hospital, a 1525 bedded tertiary care hospital located at Sawangi (Meghe), Wardha, Maharashtra in the duration of three years with total sample size of 100. The Insititutional Ethics Committee clearance has been obtained with reference number DMIMS (DU)/IEC/2022/207. This open label randomized control trial is also registered on the National Clinical Trial registration portal with reference number - CTRI/2022/10/046556.

Inclusion criteria

Children aged 1 month to 18 years, admitted in the Pediatric Intensive care unit with Serum Vitamin D level less than 20 ng/dL will be included in this study.

Exclusion criteria

The following will be excluded from the study.

1. All the cases of Rickets (already diagnosed or diagnosed on this admission)
2. Patients admitted in the PICU for monitoring purpose like post operative cases, for performance of a procedure like lumbar puncture, bone marrow aspiration etc.
3. Patients who have received Vitamin D supplementation in the last 30 days.
4. Patients with abdominal pathology.
5. Patients requiring Intensive Care Unit stay less than 24 hours.

Participants: Children aged 1 month to 18 years, admitted in the Pediatric Intensive care unit with Serum Vitamin D level less than 20 ng/dL.

Intervention: Single high dose Vitamin-D orally or via nasogastric tube.

Comparison: No supplementation of Vitamin-D.

Outcome: Short term outcome in form of number of days of Paediatric Intensive Care Unit stay, duration of mechanical ventilation, occurrence of Hospital acquired infection like Ventilator Associated Pneumonia and Central Line Associated Blood Stream Infection, Acute Kidney Injury, Multiorgan dysfunction, maximum Vasoactive-Inotrope Score and mortality.

All the children admitted in the PICU will be screened using exclusion/inclusion criteria. After excluding those children, the Serum Vitamin D level of the study group will be measured in the hospital laboratory. Children with serum Vitamin D level less than 20 ng/dL will be included in the study. Children included in the study will undergo computer generated randomization into two groups: Group A receiving the Standard treatment protocol along with 10,000 IU/kg to maximum up to 4,00,000 IU single dose Vitamin D via mouth or through the nasogastric tube and Group B receiving the Standard treatment protocol. The participants will be registered after obtaining the written parental consent. Randomization will be carried out using the WINPEPI software, and the patients will be allocated a case number and randomized. All the children will be divided equally between the experimental or research group (Group A) and the control group (Group B).

Nutritional status assessment in both the groups will be done as per WHO criteria in which wasting is defined as weight for height (gender specific) to be less than -2 standard deviation on the growth chart and stunting is defined as height for age (gender specific) to be less than -2 standard deviation on the growth chart. The baseline blood investigations done in critically ill children like Complete Blood Count, Liver Function Test, Kidney Function Test and Serum Lactate levels, coagulation profile along with inflammatory markers such as C-Reactive Protein and Lactic Dehydrogenase will be sent on Day 0 (Day of admission) and Day 3 of admission of both the groups (before and after administration of Vitamin D in Group B). Urinary calcium-creatinine ratio will be done on day 3 in Group A to check for hypervitaminosis D. The multiorgan dysfunction will be assessed by Pediatric Logistic Organ Dysfunction Logistic- 2 scoring system on day 0 and day 3. The magnitude of requirement of ionotropic support will be assessed by Vasoactive-Ionotropic Score, the maximum score will be considered for comparison in both the groups. Acute Kidney Injury will be defined based on Urine Output and serum creatinine level as per Pediatric RIFLE criteria.

The outcome of both the groups in form of number of days of Paediatric Intensive Care Unit stay, duration of mechanical ventilation, occurrence of Hospital acquired infection like Ventilator Associated Pneumonia and Central Line Associated Blood Stream Infection, Acute Kidney Injury, Multiorgan dysfunction, maximum Vasoactive-Inotrope Score and mortality will be noted and compared in both the groups. End of the study will be considered at the day of discharge or mortality of the patient. Group B will receive the therapeutic dose of Vitamin D at the end of the study. All the data will be added to a Microsfot Excel spreadsheet. Results and interpretation will be determined on the basis of the obtained observation. The methodology is been depicted in a flowchart in Figure 1.

Figure 1. Flowchart depicting the methodology of the proposed study.

Statistical analysis

STATA 12 software will be used to analyse data. The graphs will be done using Microsoft Excel 2007. Numerical data will be summarized using means and standard deviations. The baseline measures will be compared using the paired-samples, two-sided t- test. PeLOd 2 scores and VIS across groups will be compared using the analysis of variance (ANOVA) test. Scheffe’s test will be used for post-hoc comparison to find out the presence of any significant differences between groups. P values <0.05 will be considered significant.

Study status

The recruitment of the children began on 01 April 2023. As of publication, 16 patients have been included and randomized into Group A and Group B.

Discussion

In literature, benefits of Vitamin D as a fat soluble vitamin in calcium and bone metabolism is well known but its pleotropic functions and its actions like a steroid hormone are lesser known. With recent research studies, these lesser known functions of Vitamin D are becoming evident. Vitamin D has a immunomodulatory function as it helps in regulating the cellular proliferation, differentiation, apoptosis and angiogenesis which can be crucial in a critically ill child. There have been many studies conducted to determine the outcome of Vitamin D deficient critically ill children but the outcome of these children on supplementation of Vitamin D is less studied upon.

Yung Wang et al.¹³ conducted a study with 150,000 IU supplementation of Vitamin D in the study group of Vitamin D deficient septic children and found that the group with supplementation had a better outcome. El Gendy et al.¹⁴ had a conducted a study like Yung Wang et al. where the study group was Vitamin D deficient septic children. Labib et al.,¹⁵ studied the outcome of supplementation of Vitamin D in deficient children with Pneumonia. These studies have categorised their study group to one particular ailment. But we want to include all the Vitamin D deficient critically ill children in our study and no one particular ailment. This is the research gap. We wish to determine the outcome in all the critically ill children irrespective of their illness.

Therefore, we have taken up this study to determine the outcome in Vitamin D deficient critically ill children after its supplementation. The supplements of Vitamin D are easily available, well tolerated and cost effective therefore this can be a novel addition to our Paediatric Intensive Care unit protocol which can improve the short term outcome of these children.

Ethics approval and consent to participate

The institutional ethics committee has granted the permission to conduct the study with reference number - DMIMS (DU)/IEC/2022/207. Consent will be obtained from all the participants in the local language while enrolling them in the study.

Data availability

No data are associated with this article.

References

1. Lan SH, Lai CC, Chang SP, et al.: Vitamin D supplementation and the outcomes of critically ill adult patients: a systematic review and meta-analysis of randomized controlled trials. Sci. Rep. 2020 Aug 31; 10(1): 1–7. Publisher Full Text
2. Nair P, Venkatesh B, Center JR: Vitamin D deficiency and supplementation in critical illness—the known knowns and known unknowns. Crit. Care. 2018 Dec; 22(1): 1–9. Publisher Full Text
3. Holick MF: Vitamin D deficiency. N. Engl. J. Med. 2007 Jul 19; 357(3): 266–281. Publisher Full Text
4. Norman AW: From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. Am. J. Clin. Nutr. 2008 Aug 1; 88(2): 491S–499S. PubMed Abstract | Publisher Full Text
5. Ponnarmeni S, Kumar Angurana S, Singhi S, et al.: Vitamin D deficiency in critically ill children with sepsis. Paediatr. Int. Child Health. 2016 Jan 2; 36(1): 15–21. PubMed Abstract | Publisher Full Text
6. Madden K, Feldman HA, Smith EM, et al.: Vitamin D deficiency in critically ill children. Pediatrics. 2012 Sep 1; 130(3): 421–428. PubMed Abstract | Publisher Full Text | Free Full Text
7. Arnson Y, Gringauz I, Itzhaky D, et al.: Vitamin D deficiency is associated with poor outcomes and increased mortality in severely ill patients. QJM. 2012 Jul 1; 105(7): 633–639. PubMed Abstract | Publisher Full Text
8. Braun A, Chang D, Mahadevappa K, et al.: Association of low serum 25-hydroxyvitamin D levels and mortality in the critically ill. Crit. Care Med. 2011 Apr; 39(4): 671–677. PubMed Abstract | Publisher Full Text | Free Full Text
9. Han JE, Jones JL, Tangpricha V, et al.: High dose vitamin D administration in ventilated intensive care unit patients: a pilot double blind randomized controlled trial. J. Clin. Transl. Endocrinol. 2016 Jun 1; 4: 59–65. PubMed Abstract | Publisher Full Text | Free Full Text
10. Singh S, Sarkar S, Gupta K, et al.: Vitamin D Supplementation in Critically Ill Patients: A Meta-Analysis of Randomized Controlled Trials. Cureus. April 30, 2022; 14(4): e24625. PubMed Abstract | Publisher Full Text
11. McNally D, Amrein K, O’Hearn K, et al.: Study protocol for a phase II dose evaluation randomized controlled trial of cholecalciferol in critically ill children with vitamin D deficiency (VITdAL-PICU study). Pilot Feasibility Stud. 2017 Dec; 3(1): 1–3. Publisher Full Text
12. McNally J, Iliriani K, Pojsupap S, et al.: Rapid normalization of vitamin D levels: a meta-analysis. Pediatrics. 2015 Jan 1; 135(1): e152–e166. PubMed Abstract | Publisher Full Text
13. Wang Y, Yang Z, Gao L, et al.: Effects of a single dose of vitamin D in septic children: a randomized, double-blinded, controlled trial. J. Int. Med. Res. 2020 Jun; 48(6): 030006052092689. Publisher Full Text
14. El-Gendy FM, Khattab AA, Naser RG, et al.: Association between vitamin D deficiency and sepsis in pediatric ICU. Menoufia Med. J. 2021 Jan 1; 34(1): 210. Publisher Full Text
15. Labib JR, Ibrahem SK, Ismail MM, et al.: Vitamin D supplementation and improvement of pneumonic children at a tertiary.

Comments on this article Comments (1)

Version 2

VERSION 2 PUBLISHED 19 Mar 2024

Revised

Comment

Version 1

VERSION 1 PUBLISHED 29 Aug 2023

Discussion is closed on this version, please comment on the latest version above.

Reader Comment 30 Nov 2023

DINESH HINGE, PEDIATRICS, JAWAHRLAL NEHARU MEDICAL COLLEGE,SAWANGI MEGHE ,WARDHA, WARDHA, India

30 Nov 2023

Reader Comment

Very useful and interesting
Competing Interests: No competing interests were disclosed.
Very useful and interesting
Very useful and interesting
Competing Interests: No competing interests were disclosed. Close
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Discussion is closed on this version, please comment on the latest version above.

Author details Author details

¹ Pediatrics, Jawaharlal Nehru Medical College, Wardha, Maharashtra, 442001, India

Keta Vagha
Roles: Data Curation, Methodology, Project Administration, Writing – Original Draft Preparation

Sham Lohiya
Roles: Conceptualization, Writing – Review & Editing

Jayant Vagha
Roles: Writing – Review & Editing

Sunita Vagha
Roles: Supervision, Writing – Review & Editing

Amar Taksande
Roles: Writing – Review & Editing

Richa Chaudhary
Roles: Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

Funding has been received from the Research and Development Department, Datta Meghe Institute of Higher Education and Research (DMIHER(DU) R&D/2022/511).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Article Versions (2)

version 2

Revised

Published: 19 Mar 2024, 12:1047

https://doi.org/10.12688/f1000research.138765.2

version 1

Published: 29 Aug 2023, 12:1047

https://doi.org/10.12688/f1000research.138765.1

© 2023 Vagha K et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Vagha K, Lohiya S, Vagha J et al. Study protocol for supplementation of single high dose Vitamin D in deficient critically ill children and assessment of their short-term outcome: An open label randomized control trial [version 1; peer review: 1 approved with reservations, 1 not approved]. F1000Research 2023, 12:1047 (https://doi.org/10.12688/f1000research.138765.1)

NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.

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Open Peer Review

Version 1

VERSION 1

PUBLISHED 29 Aug 2023

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Reviewer Report 05 Oct 2023

Dayre McNally, University of Ottawa, Ottawa, Canada

Approved with Reservations

https://doi.org/10.5256/f1000research.151991.r205666

This study will add value to the field. Congrats to the team for identifying this question and seeking to help provide an answer.

However, there are aspects of the report that warrant clarification. See comments below. In particular be clear what the primary clinical outcome will be AND how the sample size was calculated. I also did not follow the rationale for some of the statistical plan.

Abstract

Capitalization on words and phrases (was the intention to then provide an acronym)
Make it more clear when you refer to vitamin D you are talking about cholecalciferol
Urine calcium:creatinine levels are a poor marker/indicator of hypervitaminosis. Multiple pediatric and adult studies have not shown a relationship between receipt of high dose vitamin D and urine calcium levels. More related to critical illness and Lasix
What does “the outcome of both groups will be assessed” mean. What is the primary?
No need to mention Microsoft excel sheet in abstract.
Abstract should indicate proposed sample size
The line “Results and interpretation will be determined on the basis of the obtained observation.” Is not sufficiently clear. Remove or improve

Introduction

Remove etc from the line” The pleotropic functions of Vitamin D include regulation of expression of genes in many organs like immune cells, brain, colon, kidneys etc”
Improve on the line:” These non-skeletal actions of vitamin D are similar to that of steroid hormones therefore Vitamin D is considered equivalent to a steroid hormone than just a vitamin”
What is meant by “higher intensive care scores “. Are you referring to PRISM, PIM etc? if so, consider providing examples
Agree with the point of the sentence, but it needs improvement: “There have been many studies conducted to determine the outcome of critically ill Vitamin D deficient children but there is a sparse data about the outcome of these children after supplementation of Vitamin D therefore we wish to take up this study. “ consider changing to state sparse data on whether modifying vitamin D status, influences outcome. Remove the comment about “we wish to take up”
Clarify two points in the line: “A systematic review and meta-analysis conducted by Mc Nally et al. studied more than one hundred research studies, from which it was inferred that Vitamin D at a dose of 10,000 IU/Kg to maximum up to 400,000 IU is associated with no adverse effects.”. These were 100 interventional trials, and that the level would raise levels into the high normal range in 2-3 days
Find a way to combine the following two sentences: Therefore in our study we will be using this dosing regimen.¹² With this background, we aim to conduct an open label Randomized Control Trial to study the short-term outcome of Vitamin D deficient critically ill children after supplementation of a single high dose oral Vitamin D.

Methods

Are there three objectives or two? “The main objective of this study is to assess the short-term outcome of Vitamin D deficient critically ill children after supplementation of single high dose oral Vitamin D. Secondly, to determine the prevalence of Vitamin D deficiency in critically ill children in our area (Central India) and lastly, to assess the effect of single high dose oral Vitamin D supplementation on the immediate outcome.”
- Determine prevalence
- Determine whether supplementation influences short term outcome.
It is customary to be more clear what the primary outcome measure is for objective
Be more clear the study is being conducted in India (say the country)
Be more clear the vitamin D level you are referring to is 25 hydroxyvitamin D
Can you be more clear what type of dosing you are referring to when you say: “Patients who have received Vitamin D supplementation in the last 30 days.” Also I do not see that it matters if they received vitamin D in the past, if they are vitamin D deficient at time of PICU admission
Can you clarify whether it would be unacceptable for them to receive ANY vitamin D. In our setting it would be unacceptable for us to not allow ANY vitamin D supplementation as it is standard of care to receive 400-600 IU/day (which takes a month or more to raise levels)
Outcome: While it would usual for a study to report on multiple outcomes, it is unusual for a study not to be clear on a primary, secondary and then a set a tertiary outcomes.
Please fix the error in the sentence: Group A receiving the Standard treatment protocol along with 10,000 IU/kg to maximum up to 4,00,000 IU single
As some of the patient are teenage, and the criteria do not clearly make it evident patients are intubated and/or incapacitated should consent and assent be considered as well
Provide the reference or citation for the line: “Nutritional status assessment in both the groups will be done as per WHO criteria in which wasting is defined as weight for height (gender specific) to be less than -2 standard deviation on the growth chart and stunting is defined as height for age (gender specific) to be less than -2 standard deviation on the growth chart”
Please re-evaluate how the dates of blood collection are described. Is day zero the day of randomization or admission? Is day 3, day 3 of admission or after receipt of drug
In the description of group B, can it made be very clear whether they will receive a placebo or not.
Hypervitaminosis is usually measured using 25OHD. There is no clearly established threshold for definition
When describing scores and states such as AKI and Inotrope score, provide citations so the reader can know precisely how you will approach measurement
“End of the study will be considered at the day of discharge or mortality of the patient” Do you mean PICU or hospital?
Again no need to mention excel
Main of your outcomes will NOT be normally distributed and reporting as means and analyzing using t test will not be appropriate
I don’t understand the need for ANOVA in this two arm study. Are there three or more times points for analysis? Same re: Scheffe’s test

Discussion

In the discussion there is a paragraph: “Yung Wang et al.¹³ conducted a study with 150,000 IU supplementation of Vitamin D in the study group of Vitamin D deficient septic children and found that the group with supplementation had a better outcome. El Gendy et al.¹⁴ had a conducted a study like Yung Wang et al. where the study group was Vitamin D deficient septic children. Labib et al.,¹⁵ studied the outcome of supplementation of Vitamin D in deficient children with Pneumonia.” It is not clear which studies are interventional and which are observational. You are also missing details on the citation for the Labib study.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Partly
Are sufficient details of the methods provided to allow replication by others?

Partly
Are the datasets clearly presented in a useable and accessible format?

Not applicable

Competing Interests: I am running a similar trial in Canada, a phase III double blind placebo controlled study that intends to recruit 766 patients. We are presently at 380.

Reviewer Expertise: 15 years of clinical trial experience including vitamin D supplementation in PICU

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Author Response 04 Apr 2024

Keta Vagha, Pediatrics, Jawaharlal Nehru Medical College, Wardha, 442001, India

04 Apr 2024

Author Response

I wish to express my sincere gratitude for your thoughtful review of the manuscript. Rest assured, I highly value your insights, and I am committed to incorporating all of your ... Continue reading I wish to express my sincere gratitude for your thoughtful review of the manuscript. Rest assured, I highly value your insights, and I am committed to incorporating all of your corrections diligently. The necessary adjustments will be made, and I am eager to resubmit the refined manuscript promptly. Thank you once again for your invaluable feedback.
I wish to express my sincere gratitude for your thoughtful review of the manuscript. Rest assured, I highly value your insights, and I am committed to incorporating all of your corrections diligently. The necessary adjustments will be made, and I am eager to resubmit the refined manuscript promptly. Thank you once again for your invaluable feedback.
Competing Interests: No competing interests were disclosed. Close
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COMMENTS ON THIS REPORT

Author Response 04 Apr 2024

Keta Vagha, Pediatrics, Jawaharlal Nehru Medical College, Wardha, 442001, India

04 Apr 2024

Author Response

I wish to express my sincere gratitude for your thoughtful review of the manuscript. Rest assured, I highly value your insights, and I am committed to incorporating all of your ... Continue reading I wish to express my sincere gratitude for your thoughtful review of the manuscript. Rest assured, I highly value your insights, and I am committed to incorporating all of your corrections diligently. The necessary adjustments will be made, and I am eager to resubmit the refined manuscript promptly. Thank you once again for your invaluable feedback.
I wish to express my sincere gratitude for your thoughtful review of the manuscript. Rest assured, I highly value your insights, and I am committed to incorporating all of your corrections diligently. The necessary adjustments will be made, and I am eager to resubmit the refined manuscript promptly. Thank you once again for your invaluable feedback.
Competing Interests: No competing interests were disclosed. Close
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Reviewer Report 20 Sep 2023

Tushar Jagzape, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), Raipur, Chhattisgarh, India

Not Approved

https://doi.org/10.5256/f1000research.151991.r202369

The researchers are doing a randomized controlled trial (open label) to study the effect of single high dose of vitamin D in vitamin D deficient children admitted to the Pediatric intensive care unit.
Following are my observations:

The authors have chosen a very wide age range (1 month to 18 years). The cause of morbidity and morbidity in different age groups is different. Hence the researchers should at least use stratified sampling or quota sampling in order to avoid skewed data.
The authors have not specified any severity of the illness, except that the patient should be in the ICU for more than 24 hours and not pre-operatively or post operatively. It would be better if a specific cut off of pSOFA score or PeLOd2 scores are used for inclusion and exclusion criteria.
Sample size calculation is not mentioned. Why only 100 patients are being studied?
Better to use block randomization.
The data analysis plan does not mention if it would be a per protocol analysis or intention to treat analysis.
The most important flaw in the study plan is withholding Vitamin D supplementation in the control group. At one place it has also been mentioned that the other group will be supplemented vitamin D at the end of the study (which is either discharge or death). It is ethically not correct to deny treatment, when it is available just for the research purpose.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

No
Are the datasets clearly presented in a useable and accessible format?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: General Pediatrics, Ethics, Medical education

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

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Author Response 04 Apr 2024

Keta Vagha, Pediatrics, Jawaharlal Nehru Medical College, Wardha, 442001, India

04 Apr 2024

Author Response

I would like to express my sincere appreciation for your thoughtful review of the manuscript. I would like to address a few misunderstandings regarding the drafting of the manuscript:

... Continue reading I would like to express my sincere appreciation for your thoughtful review of the manuscript. I would like to address a few misunderstandings regarding the drafting of the manuscript:

1. Regarding the impact of age on the modulation of immunity by Vitamin D at the cellular level, it is important to note that Vitamin D plays a significant role in cellular-level modulation across various diseases, rendering the age factor less influential. This aspect has been elucidated in the manuscript.

2. The sample size calculation was initially included in previous drafts but was subsequently edited out by preliminary editors. I acknowledge this oversight and assure you that it will be reinstated in the revised version.

3. Notably, the sampling technique has been refined and enhanced in the updated version of the manuscript.

4. Your ethical concern about the absence of vitamin D supplementation in the control group has been duly addressed. In the revised manuscript, a regular dose of vitamin D has been incorporated, assuaging the previously raised ethical concern.

While it is disheartening that the manuscript was rejected due to misinterpretations, I acknowledge your genuine concerns. I regret any confusion and wish to highlight that the intent is not to challenge the decision but to offer clarifications and improvements.

I understand your perspective on publishing the study protocol to solicit feedback from esteemed faculty. I appreciate your suggestion and am open to exploring such avenues in the future. Nevertheless, I am grateful for the time and consideration you have dedicated to the manuscript review. Thank you for your valuable insights, and I am committed to addressing the concerns raised in the revised submission.
I would like to express my sincere appreciation for your thoughtful review of the manuscript. I would like to address a few misunderstandings regarding the drafting of the manuscript:

1. Regarding the impact of age on the modulation of immunity by Vitamin D at the cellular level, it is important to note that Vitamin D plays a significant role in cellular-level modulation across various diseases, rendering the age factor less influential. This aspect has been elucidated in the manuscript.

2. The sample size calculation was initially included in previous drafts but was subsequently edited out by preliminary editors. I acknowledge this oversight and assure you that it will be reinstated in the revised version.

3. Notably, the sampling technique has been refined and enhanced in the updated version of the manuscript.

4. Your ethical concern about the absence of vitamin D supplementation in the control group has been duly addressed. In the revised manuscript, a regular dose of vitamin D has been incorporated, assuaging the previously raised ethical concern.

While it is disheartening that the manuscript was rejected due to misinterpretations, I acknowledge your genuine concerns. I regret any confusion and wish to highlight that the intent is not to challenge the decision but to offer clarifications and improvements.

I understand your perspective on publishing the study protocol to solicit feedback from esteemed faculty. I appreciate your suggestion and am open to exploring such avenues in the future. Nevertheless, I am grateful for the time and consideration you have dedicated to the manuscript review. Thank you for your valuable insights, and I am committed to addressing the concerns raised in the revised submission.
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Author Response 04 Apr 2024

Keta Vagha, Pediatrics, Jawaharlal Nehru Medical College, Wardha, 442001, India

04 Apr 2024

Author Response

I would like to express my sincere appreciation for your thoughtful review of the manuscript. I would like to address a few misunderstandings regarding the drafting of the manuscript:

... Continue reading I would like to express my sincere appreciation for your thoughtful review of the manuscript. I would like to address a few misunderstandings regarding the drafting of the manuscript:

1. Regarding the impact of age on the modulation of immunity by Vitamin D at the cellular level, it is important to note that Vitamin D plays a significant role in cellular-level modulation across various diseases, rendering the age factor less influential. This aspect has been elucidated in the manuscript.

2. The sample size calculation was initially included in previous drafts but was subsequently edited out by preliminary editors. I acknowledge this oversight and assure you that it will be reinstated in the revised version.

3. Notably, the sampling technique has been refined and enhanced in the updated version of the manuscript.

4. Your ethical concern about the absence of vitamin D supplementation in the control group has been duly addressed. In the revised manuscript, a regular dose of vitamin D has been incorporated, assuaging the previously raised ethical concern.

While it is disheartening that the manuscript was rejected due to misinterpretations, I acknowledge your genuine concerns. I regret any confusion and wish to highlight that the intent is not to challenge the decision but to offer clarifications and improvements.

I understand your perspective on publishing the study protocol to solicit feedback from esteemed faculty. I appreciate your suggestion and am open to exploring such avenues in the future. Nevertheless, I am grateful for the time and consideration you have dedicated to the manuscript review. Thank you for your valuable insights, and I am committed to addressing the concerns raised in the revised submission.
I would like to express my sincere appreciation for your thoughtful review of the manuscript. I would like to address a few misunderstandings regarding the drafting of the manuscript:

1. Regarding the impact of age on the modulation of immunity by Vitamin D at the cellular level, it is important to note that Vitamin D plays a significant role in cellular-level modulation across various diseases, rendering the age factor less influential. This aspect has been elucidated in the manuscript.

2. The sample size calculation was initially included in previous drafts but was subsequently edited out by preliminary editors. I acknowledge this oversight and assure you that it will be reinstated in the revised version.

3. Notably, the sampling technique has been refined and enhanced in the updated version of the manuscript.

4. Your ethical concern about the absence of vitamin D supplementation in the control group has been duly addressed. In the revised manuscript, a regular dose of vitamin D has been incorporated, assuaging the previously raised ethical concern.

While it is disheartening that the manuscript was rejected due to misinterpretations, I acknowledge your genuine concerns. I regret any confusion and wish to highlight that the intent is not to challenge the decision but to offer clarifications and improvements.

I understand your perspective on publishing the study protocol to solicit feedback from esteemed faculty. I appreciate your suggestion and am open to exploring such avenues in the future. Nevertheless, I am grateful for the time and consideration you have dedicated to the manuscript review. Thank you for your valuable insights, and I am committed to addressing the concerns raised in the revised submission.
Competing Interests: No competing interests were disclosed. Close
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Version 2

VERSION 2 PUBLISHED 19 Mar 2024

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VERSION 1 PUBLISHED 29 Aug 2023

Discussion is closed on this version, please comment on the latest version above.

Reader Comment 30 Nov 2023

DINESH HINGE, PEDIATRICS, JAWAHRLAL NEHARU MEDICAL COLLEGE,SAWANGI MEGHE ,WARDHA, WARDHA, India

30 Nov 2023

Reader Comment

Very useful and interesting
Competing Interests: No competing interests were disclosed.
Very useful and interesting
Very useful and interesting
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Version 2 (revision) 19 Mar 24	read	read
Version 1 29 Aug 23	read	read

Tushar Jagzape, All India Institute of Medical Sciences (AIIMS), Raipur, India
Dayre McNally, University of Ottawa, Ottawa, Canada

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16 Apr 2024 | for Version 2

Tushar Jagzape, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), Raipur, Chhattisgarh, India

2 Views Cite this report Responses(0)

Approved

The revision made are satisfactory and addresses the major concern which was raised previously.
The following one more modification should be done in the study protocol, so that the results are not biased and the patient in control group is not denied the correct treatment.
Comparision group is receiving 400 IU for less than 1 year old child and 800 IU for more than 1 year. These are maintenance or supplement doses and not for deficiency. Please modify the dose for vitamin D deficiency. May use the IAP recommended dose of 2000IU below 1 year and 3000IU for older children (in the control group).
Thank you. Regards

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No competing interests were disclosed.

Reviewer Expertise

General Pediatrics, Ethics, Medical education, Pediatric allergy and asthma

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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02 Apr 2024 | for Version 2

Dayre McNally, University of Ottawa, Ottawa, Canada

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Approved With Reservations

Thanks for resending.

I have a few suggestions for this article and study:

1. I suggest the authors indicate what outcome is their primary outcome. As of now they have a list of "primary" outcomes

2. Linked to #1, they probably should justify the sample size of 100. In our field (PCC) a RCT of 100 is over double the standard size. However, it remains important to justify the sample size. How was it calculated?

3. They indicate 3 years study duration and 16 patients included and randomized. Most PCC RCTs only recruit 1-2 patients per site per month. They might want to more clearly indicate whether they will stop at 3 years if they do not have 100 enrolled.

Competing Interests

I am the PI on a Canadian multicentre study on the same topic.

Reviewer Expertise

15 years of clinical trial experience including vitamin D supplementation in PICU

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10 Views

05 Oct 2023 | for Version 1

Dayre McNally, University of Ottawa, Ottawa, Canada

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Approved With Reservations

Capitalization on words and phrases (was the intention to then provide an acronym)
Make it more clear when you refer to vitamin D you are talking about cholecalciferol
Urine calcium:creatinine levels are a poor marker/indicator of hypervitaminosis. Multiple pediatric and adult studies have not shown a relationship between receipt of high dose vitamin D and urine calcium levels. More related to critical illness and Lasix
What does “the outcome of both groups will be assessed” mean. What is the primary?
No need to mention Microsoft excel sheet in abstract.
Abstract should indicate proposed sample size
The line “Results and interpretation will be determined on the basis of the obtained observation.” Is not sufficiently clear. Remove or improve

Introduction

Remove etc from the line” The pleotropic functions of Vitamin D include regulation of expression of genes in many organs like immune cells, brain, colon, kidneys etc”
Improve on the line:” These non-skeletal actions of vitamin D are similar to that of steroid hormones therefore Vitamin D is considered equivalent to a steroid hormone than just a vitamin”
What is meant by “higher intensive care scores “. Are you referring to PRISM, PIM etc? if so, consider providing examples
Agree with the point of the sentence, but it needs improvement: “There have been many studies conducted to determine the outcome of critically ill Vitamin D deficient children but there is a sparse data about the outcome of these children after supplementation of Vitamin D therefore we wish to take up this study. “ consider changing to state sparse data on whether modifying vitamin D status, influences outcome. Remove the comment about “we wish to take up”
Clarify two points in the line: “A systematic review and meta-analysis conducted by Mc Nally et al. studied more than one hundred research studies, from which it was inferred that Vitamin D at a dose of 10,000 IU/Kg to maximum up to 400,000 IU is associated with no adverse effects.”. These were 100 interventional trials, and that the level would raise levels into the high normal range in 2-3 days
Find a way to combine the following two sentences: Therefore in our study we will be using this dosing regimen.¹² With this background, we aim to conduct an open label Randomized Control Trial to study the short-term outcome of Vitamin D deficient critically ill children after supplementation of a single high dose oral Vitamin D.

Methods

Are there three objectives or two? “The main objective of this study is to assess the short-term outcome of Vitamin D deficient critically ill children after supplementation of single high dose oral Vitamin D. Secondly, to determine the prevalence of Vitamin D deficiency in critically ill children in our area (Central India) and lastly, to assess the effect of single high dose oral Vitamin D supplementation on the immediate outcome.”
- Determine prevalence
- Determine whether supplementation influences short term outcome.
It is customary to be more clear what the primary outcome measure is for objective
Be more clear the study is being conducted in India (say the country)
Be more clear the vitamin D level you are referring to is 25 hydroxyvitamin D
Can you be more clear what type of dosing you are referring to when you say: “Patients who have received Vitamin D supplementation in the last 30 days.” Also I do not see that it matters if they received vitamin D in the past, if they are vitamin D deficient at time of PICU admission
Can you clarify whether it would be unacceptable for them to receive ANY vitamin D. In our setting it would be unacceptable for us to not allow ANY vitamin D supplementation as it is standard of care to receive 400-600 IU/day (which takes a month or more to raise levels)
Outcome: While it would usual for a study to report on multiple outcomes, it is unusual for a study not to be clear on a primary, secondary and then a set a tertiary outcomes.
Please fix the error in the sentence: Group A receiving the Standard treatment protocol along with 10,000 IU/kg to maximum up to 4,00,000 IU single
As some of the patient are teenage, and the criteria do not clearly make it evident patients are intubated and/or incapacitated should consent and assent be considered as well
Provide the reference or citation for the line: “Nutritional status assessment in both the groups will be done as per WHO criteria in which wasting is defined as weight for height (gender specific) to be less than -2 standard deviation on the growth chart and stunting is defined as height for age (gender specific) to be less than -2 standard deviation on the growth chart”
Please re-evaluate how the dates of blood collection are described. Is day zero the day of randomization or admission? Is day 3, day 3 of admission or after receipt of drug
In the description of group B, can it made be very clear whether they will receive a placebo or not.
Hypervitaminosis is usually measured using 25OHD. There is no clearly established threshold for definition
When describing scores and states such as AKI and Inotrope score, provide citations so the reader can know precisely how you will approach measurement
“End of the study will be considered at the day of discharge or mortality of the patient” Do you mean PICU or hospital?
Again no need to mention excel
Main of your outcomes will NOT be normally distributed and reporting as means and analyzing using t test will not be appropriate
I don’t understand the need for ANOVA in this two arm study. Are there three or more times points for analysis? Same re: Scheffe’s test

Discussion

In the discussion there is a paragraph: “Yung Wang et al.¹³ conducted a study with 150,000 IU supplementation of Vitamin D in the study group of Vitamin D deficient septic children and found that the group with supplementation had a better outcome. El Gendy et al.¹⁴ had a conducted a study like Yung Wang et al. where the study group was Vitamin D deficient septic children. Labib et al.,¹⁵ studied the outcome of supplementation of Vitamin D in deficient children with Pneumonia.” It is not clear which studies are interventional and which are observational. You are also missing details on the citation for the Labib study.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Partly
Are sufficient details of the methods provided to allow replication by others?

Partly
Are the datasets clearly presented in a useable and accessible format?

Not applicable

Competing Interests

I am running a similar trial in Canada, a phase III double blind placebo controlled study that intends to recruit 766 patients. We are presently at 380.

Reviewer Expertise

15 years of clinical trial experience including vitamin D supplementation in PICU

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17 Views

20 Sep 2023 | for Version 1

Tushar Jagzape, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), Raipur, Chhattisgarh, India

17 Views Cite this report Responses(1)

Not Approved

The authors have chosen a very wide age range (1 month to 18 years). The cause of morbidity and morbidity in different age groups is different. Hence the researchers should at least use stratified sampling or quota sampling in order to avoid skewed data.
The authors have not specified any severity of the illness, except that the patient should be in the ICU for more than 24 hours and not pre-operatively or post operatively. It would be better if a specific cut off of pSOFA score or PeLOd2 scores are used for inclusion and exclusion criteria.
Sample size calculation is not mentioned. Why only 100 patients are being studied?
Better to use block randomization.
The data analysis plan does not mention if it would be a per protocol analysis or intention to treat analysis.
The most important flaw in the study plan is withholding Vitamin D supplementation in the control group. At one place it has also been mentioned that the other group will be supplemented vitamin D at the end of the study (which is either discharge or death). It is ethically not correct to deny treatment, when it is available just for the research purpose.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

No
Are the datasets clearly presented in a useable and accessible format?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

General Pediatrics, Ethics, Medical education

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Author Response

04 Apr 2024

Keta Vagha, Pediatrics, Jawaharlal Nehru Medical College, Wardha, 442001, India

I would like to express my sincere appreciation for your thoughtful review of the manuscript. I would like to address a few misunderstandings regarding the drafting of the manuscript:

1. Regarding the impact of age on the modulation of immunity by Vitamin D at the cellular level, it is important to note that Vitamin D plays a significant role in cellular-level modulation across various diseases, rendering the age factor less influential. This aspect has been elucidated in the manuscript.

2. The sample size calculation was initially included in previous drafts but was subsequently edited out by preliminary editors. I acknowledge this oversight and assure you that it will be reinstated in the revised version.

3. Notably, the sampling technique has been refined and enhanced in the updated version of the manuscript.

4. Your ethical concern about the absence of vitamin D supplementation in the control group has been duly addressed. In the revised manuscript, a regular dose of vitamin D has been incorporated, assuaging the previously raised ethical concern.

While it is disheartening that the manuscript was rejected due to misinterpretations, I acknowledge your genuine concerns. I regret any confusion and wish to highlight that the intent is not to challenge the decision but to offer clarifications and improvements.

I understand your perspective on publishing the study protocol to solicit feedback from esteemed faculty. I appreciate your suggestion and am open to exploring such avenues in the future. Nevertheless, I am grateful for the time and consideration you have dedicated to the manuscript review. Thank you for your valuable insights, and I am committed to addressing the concerns raised in the revised submission.

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Competing Interests

No competing interests were disclosed.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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[2] 2. Nair P, Venkatesh B, Center JR: Vitamin D deficiency and supplementation in critical illness—the known knowns and known unknowns. Crit. Care. 2018 Dec; 22(1): 1–9. Publisher Full Text

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[8] 8. Braun A, Chang D, Mahadevappa K, et al.: Association of low serum 25-hydroxyvitamin D levels and mortality in the critically ill. Crit. Care Med. 2011 Apr; 39(4): 671–677. PubMed Abstract | Publisher Full Text | Free Full Text

[9] 9. Han JE, Jones JL, Tangpricha V, et al.: High dose vitamin D administration in ventilated intensive care unit patients: a pilot double blind randomized controlled trial. J. Clin. Transl. Endocrinol. 2016 Jun 1; 4: 59–65. PubMed Abstract | Publisher Full Text | Free Full Text

[10] 10. Singh S, Sarkar S, Gupta K, et al.: Vitamin D Supplementation in Critically Ill Patients: A Meta-Analysis of Randomized Controlled Trials. Cureus. April 30, 2022; 14(4): e24625. PubMed Abstract | Publisher Full Text

[11] 11. McNally D, Amrein K, O’Hearn K, et al.: Study protocol for a phase II dose evaluation randomized controlled trial of cholecalciferol in critically ill children with vitamin D deficiency (VITdAL-PICU study). Pilot Feasibility Stud. 2017 Dec; 3(1): 1–3. Publisher Full Text

[12] 12. McNally J, Iliriani K, Pojsupap S, et al.: Rapid normalization of vitamin D levels: a meta-analysis. Pediatrics. 2015 Jan 1; 135(1): e152–e166. PubMed Abstract | Publisher Full Text

[13] 13. Wang Y, Yang Z, Gao L, et al.: Effects of a single dose of vitamin D in septic children: a randomized, double-blinded, controlled trial. J. Int. Med. Res. 2020 Jun; 48(6): 030006052092689. Publisher Full Text

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[15] 15. Labib JR, Ibrahem SK, Ismail MM, et al.: Vitamin D supplementation and improvement of pneumonic children at a tertiary.

Study protocol for supplementation of single high dose Vitamin D in deficient critically ill children and assessment of their short-term outcome: An open label randomized control trial

Abstract

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Introduction

Objectives

Methods

Research questions

Study design

Inclusion criteria

Exclusion criteria

Figure 1. Flowchart depicting the methodology of the proposed study.

Statistical analysis

Study status

Discussion

Ethics approval and consent to participate

Data availability

References

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